Bortezomib-resistance is associated with increased levels of proteasome subunits and apoptosis-avoidance

Wu, Yi-Ting; Yang, Jingsi; Saitsu, Hirotomo

doi:10.18632/oncotarget.12731

Cited by 36 publications

(29 citation statements)

References 50 publications

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“…Proteasome inhibitors represent a new class of promising therapeutic drugs in cancer 2 , 3 . However, although several preclinical studies have shown that proteasome inhibition by bortezomib could represent a viable therapeutic strategy for treatment of HCC 10 – 12 , clinical results obtained in patients with unresectable HCC have been disappointing 13 .…”

Section: Discussionmentioning

confidence: 99%

“…At the molecular level, bortezomib treatment induces cell death through endoplasmic reticulum (ER) stress induction 4 – 7 , nuclear factor kappa B inhibition 8 , and caspase-8 activation 9 . However, although preclinical results have shown that bortezomib has antitumor effects in HCC 10 – 12 , a multicenter single-arm phase II trial conducted in cases of unresectable HCC showed that although bortezomib is well tolerated, it lacks significant activity 13 . Moreover, in many cases patients treated with bortezomib rapidly develop drug resistance, the mechanisms of which are poorly understood 14 .…”

Section: Introductionmentioning

confidence: 99%

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Preclinical evaluation of antitumor activity of the proteasome inhibitor MLN2238 (ixazomib) in hepatocellular carcinoma cells

et al. 2018

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Hepatocellular carcinoma (HCC) is one of the common malignancies and is an increasingly important cause of cancer death worldwide. Surgery, chemotherapy, and radiation therapy extend the 5-year survival limit in HCC patients by only 6%. Therefore, there is a need to develop new therapeutic approaches for the treatment of this disease. The orally bioavailable proteasome inhibitor MLN2238 (ixazomib) has been demonstrated to have anticancer activity. In the present study, we investigated the preclinical therapeutic efficacy of MLN2238 in HCC cells through in vitro and in vivo models, and examined its molecular mechanisms of action. MLN2238 inhibited cell viability in human HCC cells HepG2, Hep3B, and SNU475 in a time- and dose-dependent manner. Flow cytometry analysis demonstrated that MLN2238 induced G2/M cell cycle arrest and cellular apoptosis in HCC cells. Cell cycle arrest was associated with increased expression levels of p21 and p27. MLN2238-induced apoptosis was confirmed by caspase-3/7 activation, PARP cleavage and caspase-dependent β-catenin degradation. In addition, MLN2238 activated ER stress genes in HCC cells and increased the expression of the stress-inducible gene nuclear protein-1. Furthermore, MLN2238 treatment induced upregulation of myeloid cell leukemia-1 (Mcl-1) protein, and Mcl-1 knockdown sensitized HCC cells to MLN2238 treatment, suggesting the contribution of Mcl-1 expression to MLN2238 resistance. This result was also confirmed using the novel Mcl-1 small molecule inhibitor A1210477. Association of A1210477 and MLN2238 determined synergistic antitumor effects in HCC cells. Finally, in vivo orally administered MLN2238 suppressed tumor growth of Hep3B cells in xenograft models in nude mice. In conclusion, our results offer hope for a new therapeutic opportunity in the treatment of HCC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of antitumor activity of the proteasome inhibitor MLN2238 (ixazomib) in hepatocellular carcinoma cells

et al. 2018

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“…Despite initial clinical success in treating MM, many patients eventually relapsed from bortezomib therapy due to resistance development 27,28 . Bortezomib resistance is caused due to mutations in the binding pocket of PSMB5 subunit of proteasome that resulted in impaired drug binding.…”

Section: Discussionmentioning

confidence: 99%

Silencing of SENP2 in Multiple Myeloma Induces Bortezomib Resistance by Activating NF-κB Through the Modulation of IκBα Sumoylation

Xie

Wang

et al. 2020

Sci Rep

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The proteasome inhibitor bortezomib is the most successfully applied chemotherapeutic drug for treating multiple myeloma. However, its clinical efficacy reduced due to resistance development. The underlying molecular mechanisms of bortezomib resistance are poorly understood. In this study, by combining in silico analysis and sgRNA library based drug resistance screening assay, we identified SENP2 (Sentrin/SUMO-specific proteases-2) as a bortezomib sensitive gene and found its expression highly downregulated in bortezomib resistant multiple myeloma patient's samples. Furthermore, down regulation of SENP2 in multiple myeloma cell line RPMI8226 alleviated bortezomib induced cell proliferation inhibition and apoptosis, whereas, overexpression of SENP2 sensitized these cells to bortezomib treatment. We further demonstrate that knockdown of SENP2 in RPMI8226 cells increased SUMO2 conjugated IκBα that resulted in the activation of NF-κB. Taken together, we report that silencing of SENP2 and consequent activation of NF-κB through the modulation of IκBα sumoylation as a novel mechanism inducing bortezomib resistance in multiple myeloma. Multiple myeloma (MM) is a malignant plasma cell tumor that account for 12% of blood malignant tumors, which is the second most commonly diagnosed hematologic malignancy 1. Despite applying multiple therapeutic drugs such as, proteasome inhibitor bortezomib 2 and immunomodulator thalidomide 3 , the median MM patient survival was only slightly improved from 3-5 years to 5-7 years 4. Moreover, MM is still featured as a recurrence and insensitive to treatment due to drug resistance development 5. The bortezomib is the first class of proteasome inhibitor approved for the treatment of MM. Bortezomib is a dipeptidyl boronic acid that reversibly binds to chymotrypsin-like catalytic subunit of 20 S proteasome and inhibits its activity 6. Proteasome plays a critical role in cellular homeostasis by degrading unwanted cellular proteins 7. The imbalance between synthesis and degradation of proteins arises due to proteasome inhibition results in the accumulation of regulatory proteins causing endoplasmic reticulum stress and activation of the unfolded protein response leading to induction of apoptosis in malignant cells via multiple mechanisms 8,9 .

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“…Recent studies of the direct mechanisms of Btz resistance were derived analyzed various tumor cell lines, including MM [ 10 , 11 ], lymphoma [ 26 ], leukemia [ 9 , 27 ], lung cancer [ 12 ], and hepatocellular carcinoma [ 14 ], with Btz. These studies suggested that Btz resistance is controlled by multiple factors, including alterations in PSMB5 expression or sequence, adjustment of biosynthesis of new proteins to reduce the ER stress [ 27 ], and upregulation of multiple proteasome subunits, such as β2 and β5 subunits, which enables cells to adapt to the selective proteasome inhibition resulting from Btz treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of CT-L activity is considered a key strategy for treating MM cells. However, several studies have proposed that the mechanism of action of Btz resistance is mainly associated with activity of the β5 subunit, such as mutations in PSMB5 (β5 subunit coding gene) [ 9 , 10 ] or upregulated expression of proteasome subunits [ 11 – 14 ]. Specifically, inhibiting the activity of the β5 subunit would not provide a sufficient anti-tumor effect in MM cases showing Btz resistance.…”

Section: Introductionmentioning

confidence: 99%

Potent anti-tumor activity of a syringolin analog in multiple myeloma: a dual inhibitor of proteasome activity targeting β2 and β5 subunits

Yoshida

Kanamori

et al. 2018

Oncotarget

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Proteasome inhibitors (PI), mainly targeting the β5 subunit of the 20S proteasome, are widely used in the treatment of multiple myeloma (MM). However, PI resistance remains an unresolved problem in the therapy of relapsed and refractory MM. To develop a new PI that targets other proteasome subunits, we examined the anti-MM activity of a novel syringolin analog, syringolog-1, which inhibits the activity of both the β5 and β2 subunits. Syringolog-1 exhibited marked cytotoxicity against various MM cell lines and anti-tumor activity towards bortezomib (Btz)-resistant MM cells through the dual inhibition of chymotrypsin-like (β5 subunit) and trypsin-like (β2 subunit) activities. MM cells, including Btz-resistant cells, showed elevated CHOP and NOXA expression after syringolog-1 treatment, indicating the induction of excessive endoplasmic reticulum stress during syringolog-1 treatment. Similar activities of syringolog-1 were also observed in freshly prepared MM cells derived from patients. To clarify the anti-tumor mechanism of dual inhibition of both the β5 and β2 subunits of the proteasome, PSMB5 and PSMB7 were co-inhibited in MM cells. This resulted in increased apoptosis of MM cells accompanied by accumulation of ubiquitinated proteins compared to inhibition of either PSMB7 or PSMB5 alone, indicating an enhanced effect by double inhibition of β2 and β5 activities. In conclusion, this syringolin analog, a dual inhibitor of proteasome β2 and β5 activities, exhibited potent anti-tumor effects on MM cells and may be useful for overcoming Btz-resistance in the treatment of MM.

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Bortezomib-resistance is associated with increased levels of proteasome subunits and apoptosis-avoidance

Cited by 36 publications

References 50 publications

Preclinical evaluation of antitumor activity of the proteasome inhibitor MLN2238 (ixazomib) in hepatocellular carcinoma cells

Preclinical evaluation of antitumor activity of the proteasome inhibitor MLN2238 (ixazomib) in hepatocellular carcinoma cells

Silencing of SENP2 in Multiple Myeloma Induces Bortezomib Resistance by Activating NF-κB Through the Modulation of IκBα Sumoylation

Potent anti-tumor activity of a syringolin analog in multiple myeloma: a dual inhibitor of proteasome activity targeting β2 and β5 subunits

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